Pre-Screening for Low Methyl Guanine Methyltransferase (MGMT) Expression Results in High Response Rates to Temozolomide (TMZ) Therapy in AML and MDS Patients.
Notice bibliographique
Résumé
Abstract Abstract 422 Introduction: Many patients with acute myeloid leukemia (AML) and high-risk myelodysplasia (MDS) are not suitable candidates for standard induction therapy, and newer treatment approaches are needed. TMZ anti-tumor activity is attributed to methylation of DNA, leading to the formation of O6-methylguanine that eventually leads to apoptosis. Expression of MethylGuanine DNA MethylTransferase (MGMT) restores normal guanine, decreasing DNA alkylation and thus anti-tumor activity of TMZ. Brandwein et al. (Leukemia 2007;21:821–4) previously demonstrated that response to TMZ in AML patients could be correlated with low MGMT expression. Thus MGMT expression prescreening could be used to identify patients more likely to respond to TMZ and provide an alternative for patients who are not candidates for standard induction therapy. Methods: We conducted a prospective multicenter study of patients with previously untreated AML and high risk MDS who were not candidates for standard induction therapy. Patient selection was based on MGMT expression as determined by Western blot in bone marrow or peripheral blood. Screening was performed by comparing the expression ratio between MGMT and b-actin protein levels. Patients with a ratio <0.25 were eligible to receive TMZ therapy 200 mg/m2/day × 7 days. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide 200 mg/m2/day × 5 days. Partial responders received a modified schedule of temozolomide 100 mg/m2/day × 21 days. Results: MGMT expression was tested in 188 patients; median age was 75 years old (range 46–94 years);62% were male. Primary diagnoses were AML (86%) and MDS (14%). Low or weak MGMT expression was detected in 46% of patient that were therefore potential candidates for TMZ therapy. Responses were evaluated in 42 patients, and were divided into 4 categories: Complete (CR/CRp), Morphologic Leukemia-Free State (MLFS), Partial (PR) Minimal (MR). Response was observed in 74% of cases including 29% CR, 10% MLFS, 19% PR and 17% MR. Prognostic factors associated with a higher response rate to temozolomide included MDS presentation, ECOG PS 0 and favorable/standard cytogenetic risk group. Induction and post-remission cycles were well-tolerated and most patients could be successfully treated on an outpatient basis. Patient who reached CR/CRp had a significantly longer median survival (>18 months) compared to those who reached MLFS, PR and MR (5.6 months). Median duration of therapy for patients reaching CR/CRp was 255 days and a majority (80%) became transfusion independent. Grade 3 and 4 toxicities were rare with the most common being fatigue (17%) and diarrhea (6%). Discussion: Pre-selection of patients based on MGMT expression level was associated with a higher response rate to TMZ as compared to previously reported unselected patients. Complete response was associated with increased survival and treatment had a favorable toxicity profile even in frail elderly patients. Targeted therapy with TMZ is feasible in patients with low MGMT expression and represents a new option for AML and MDS patients who are not candidate for standard induction therapy. Disclosures: Brandwein: Merck: Research Funding. Off Label Use: Temozolomide therapy for AML and MDS. Kassis:Merck: Research Funding. Leber:Merck: Research Funding. Howson-Jan:Merck: Research Funding. Minden:Merck: Research Funding. Galarneau:Merck: Employment. Pouliot:Merck: Employment.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».